The present invention relates to water-soluble drugs, in particular water-soluble analogues of geldanamycin, and compositions comprising the same. This invention also relates to a method of rendering water-insoluble drugs soluble in water and a method of treating cancer.
A common problem associated with drugs intended for parenteral, and especially intravenous, administration has been the solubilization of a slightly soluble or water-insoluble active ingredient (Sweetana et al., PDA J. Pharm. Sci. and Tech. 50, 330 (1995)). As a result, many drugs of potential benefit in cancer chemotherapy and other areas of therapeutics have been abandoned. Methods have been developed whereby drugs can be enveloped in micelles and placed into aqueous solutions (Hawthorne et al., J. Neurooncol., 33, 53-58 (1997)). Likewise, cosolvents and complexing agents allow some drugs to be dissolved in water (Badwan et al., U.S. Pat. No. 5,646,131). The use of these reagents, however, can be complex and have negative attributes due to the additional reagent required to dissolve the active ingredient (Sweetana et al. (1995), supra). Prodrugs also have been developed by attaching groups, such as phosphates and other conjugates, to increase their solubility and enhance their performance (Schacter et al., Cancer Chemother. Pharmacol., 34, S58 (1994); Kingston et al., U.S. Pat. No. 5,278,324).
One water-insoluble drug of potential beneficial use in cancer therapy is geldanamycin. The drug is an ansamycin isolated from the broth of Streptomyces hygroscopicus var. geldanus (DeBoer et al., Antiobiot., 23, 442 (1970)). It has been found to exert its antiproliferating and anticancer activities by binding with the heat shock protein 90 (Hsp90) chaperone and, in turn, altering the translocation properties of the tumor suppressor protein p53 (Stebbins et al., Cell, 239 (1997); Sepehrnia et al., J. Biol. Chem., 271, 15,084 (1996); Dasgupta et al., Experimental Cell Research, 29, 237 (1997)). Despite its therapeutic potential as an anticancer agent, initial studies indicate that the bioavailability of geldanamycin must be enhanced and the toxicity associated with the natural product reduced before significant progress can be made with respect to the anticancer use of geldanamycin. Chemical modifications of geldanamcyin could potentially provide analogs with improved bioactivity and bioavailability. While derivatives of geldanamycin have been developed to enhance the cancer-fighting effects of the drug, the low solubility of such derivatives have required the use of emulsifying or suspending agents in order to obtain aqueous solutions. This has tended to reduce the bioavailability of the drug, and has thereby affected its utility as an anticancer agent.
The present invention addresses these problems by providing a method of producing water-soluble analogues of water-insoluble drugs and, in particular, by providing a water-soluble analogue of the anticancer drug geldanamycin. Due to its thiol ether linkage, the analogue is expected to exhibit superior bioavailability and stability under physiological conditions.
The present invention provides a water-soluble compound of the formula 
where A is a water-insoluble drug, B1 and B2 together are a spacer moiety, and X is a polar moiety. The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the above-described compound. In addition, the present invention provides a method of treating cancer in a mammal. The method comprises administering to a mammal having cancer an effective amount of the above-described compound.
The present invention further provides a method of rendering soluble in water a water-insoluble drug. The method comprises contacting a water-insoluble drug comprising a side-chain that can react with a bifunctional linking molecule with a bifunctional linking molecule comprising a maleimido functional group to obtain a first derivative of the water-insoluble drug comprising a side-chain that comprises a maleimido functional group. The method further comprises contacting the first derivative with a polar moiety comprising a thio group (Xxe2x80x94SH) to obtain a water-soluble compound as described above.
The present invention still further provides a water-soluble compound of the formula 
or a pharmaceutically acceptable salt thereof, wherein:
R1 is an ionic moiety bound to the carbon at position 17 via a nitrogen atom,
R2 is a halo or an xe2x80x94OR8 when there is a single bond between R2 and the carbon at position 11, wherein R8 is hydrogen, a C1-C8 alkylamido, a C1-C8 alkyl, a C2-C8 alkenyl, a C2-C8 alkynyl, a C1-C8 hydroxyalkyl, a C1-C8 alkyl carbamoyl, a C1-C8 alkylcarbonyl, or an aralkyl, any of which R8 can be further substituted with one or more substituents, which can be the same or different, selected from the group consisting of a nitro, a halo, an azido, a hydroxy, an amido and an amino group, or
R2 is oxo (xe2x95x90O) or oximino (xe2x95x90NOH) when there is a double bond between R2 and the carbon at position 11,
R1 is selected from the group consisting of hydrogen and a group of the formula 
wherein R5, R6, and R7 are each independently selected from the group consisting of hydrogen, a halo, an azido, a nitro, a C1-C8 alkyl, a C1-C8 alkoxy, an aryl, a cyano, and an NR10R11R12, wherein R10, R11, and R12, are each independently selected from the group consisting of hydrogen and a C1-C3 alkyl,
R4 is selected from the group consisting of hydrogen, a halo, a C1-C8 alkylamino, and a C1-C8 dialkylamino, and the bond between the carbons at positions 4 and 5 can be a single bond or a double bond.
Also provided by the present invention is a water-soluble compound of the formula 
or a pharmaceutically acceptable salt thereof, wherein:
Y is a spacer group,
P is a polypeptide or a protein that selectively binds to the surface of a mammalian cell,
R2 is a halo or an xe2x80x94OR8 when there is a single bond between R2 and the carbon at position 11, wherein R8 is selected from the group consisting of hydrogen, a C1-C8 alkylamido, a C1-C8 alkyl, a C2-C8 alkenyl, a C2-C8 alkynyl, a C1-C8 hydroxyalkyl, a C1-C8 alkyl carbamoyl, a C1-C8 alkylcarbonyl, and an aralkyl, any of which R8 groups can be further substituted with one or more substituents, which can be the same or different, selected from the group consisting of a nitro, a halo, an azido, a hydroxy, an amido and an amino group, or
R2 is oxo (xe2x95x90O) or oximino (xe2x95x90NOH) when there is a double bond between R2 and the carbon at position 11,
R3 is selected from the group consisting of hydrogen and a group of the formula 
wherein R5, R6, and R7 are each independently selected from the group consisting of hydrogen, a halo, an azido, a nitro, a C1-C8 alkyl, a C1-C8 alkoxy, an aryl, a cyano, and an NR10R11R12, wherein R10, R11, and R12 are each independently selected from the group consisting of hydrogen and a C1-C3 alkyl,
R4 is selected from the group consisting of hydrogen, a halo, a C1-C8 alkylamino, and a C1-C8 dialkylamino, and the bond between the carbons at positions 4 and 5 can be a single bond or a double bond.